A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, ...the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.
Context:
An increasing number of studies suggest that bone marrow adipose tissue (BMAT) might play a role in the pathogenesis of osteoporosis. Our previous study of Caucasian women demonstrated that ...there is an inverse relationship between BMAT and whole-body bone mineral density (BMD). It is unknown whether visceral adipose tissue (VAT), sc adipose tissue (SAT), and skeletal muscle had an effect on the relationship between BMAT and BMD.
Objective:
In the present study we investigated the relationship between pelvic, hip, and lumbar spine BMAT with hip and lumbar spine BMD in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) sample with adjustment for whole-body magnetic resonance imaging (MRI)-measured VAT, SAT, and skeletal muscle.
Design:
T1-weighted MRI was acquired for 210 healthy African-American and Caucasian men and women (age 38–52 yr). Hip and lumbar spine BMD were measured by dual-energy x-ray absorptiometry.
Results:
Pelvic, hip, and lumbar spine BMAT had negative correlations with hip and lumbar spine BMD (r = −0.399 to −0.550, P < 0.001). The inverse associations between BMAT and BMD remained strong after adjusting for demographics, weight, skeletal muscle, SAT, VAT, total adipose tissue (TAT), menopausal status, lifestyle factors, and inflammatory markers (standardized regression coefficients = −0. 296 to −0.549, P < 0.001). Among body composition measures, skeletal muscle was the strongest correlate of BMD after adjusting for BMAT (standardized regression coefficients = 0.268–0.614, P < 0.05), with little additional contribution from weight, SAT, VAT, or total adipose tissue.
Conclusion:
In this middle-aged population, a negative relationship existed between MRI-measured BMAT and hip and lumbar spine BMD independent of demographics and body composition. These observations support the growing evidence linking BMAT with low bone density.
C-reactive protein (CRP) levels>3 mg/L and>10 mg/L are associated with high and very high cardiovascular risk, respectively, in the general population. Because rheumatoid arthritis (RA) confers ...excess cardiovascular mortality, we determined the prevalence of these CRP levels among RA patients stratified on the basis of their RA disease activity.
We evaluated physician and patient global assessments of disease activity, tender and swollen 28 joint counts, erythrocyte sedimentation rate (ESR), and CRP measured in a single clinic visit for 151 RA patients. Disease activity was calculated using the Clinical Disease Activity Index (CDAI) and the Disease Activity Score 28 Joints (DAS28-ESR and DAS28-CRP).
Median CRP level was 5.3 mg/L. 68% of patients had CRP>3 mg/L, and 25% had CRP>10 mg/L. Of those with 0-1 swollen joints (n = 56), or 0-1 tender joints (n = 81), 64% and 67%, respectively, had CRP>3 mg/L, and 23% and 20%, respectively, had CRP>10 mg/L. Of those with remission or mildly active disease by CDAI (n = 58), DAS28-ESR (n = 39), or DAS28-CRP (n = 70), 49-66% had CRP>3 mg/L, and 10-14% had CRP>10 mg/L. Of patients with moderate disease activity by CDAI (n = 51), DAS28-ESR (n = 78), or DAS28-CRP (n = 66), 67-73% had CRP>3 mg/L, and 25-33% had CRP>10 mg/L.
Even among RA patients whose disease is judged to be controlled by joint counts or standardized disease scores, a substantial proportion have CRP levels that are associated high or very high risk for future cardiovascular events in the general population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis ...independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17 +/- 0.50 mm for HIV-infected participants and 1.06 +/- 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm 95% confidence interval (CI) 0.113-0.263, P < 0.0001. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072-0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010-0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
Background Compared with controls, human immunodeficiency virus (HIV)-infected persons have a greater prevalence of kidney disease, assessed according to high cystatin C level and albuminuria, but ...not according to creatinine level. However, the clinical importance of increased cystatin C level and albuminuria in the HIV-infected population has not been studied. Study Design We conducted an observational cohort study to determine the association of kidney disease (measured according to albuminuria, cystatin C, and serum creatinine) with mortality. Setting & Participants 922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) Study. Predictor Serum cystatin C and serum creatinine levels were used to estimate glomerular filtration rates (eGFRSCysC and eGFRSCr , respectively). Albuminuria was defined as a positive urine dipstick result (≥1+) or urine albumin-creatinine ratio >30 mg/g. Outcome 5-Year mortality. Results At baseline, decreased kidney function (eGFRSCysC <60 mL/min/1.73 m2 ) or albuminuria was present in 28% of participants. After 5 years of follow-up, mortality was 48% in those with both eGFRSCysC <60 mL/min/1.73 m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73 m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory marker levels, eGFRSCysC <60 mL/min/1.73 m2 and albuminuria were associated with a nearly 2-fold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have a substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73 m2 and albuminuria accounted for 17% of the population-level attributable risk of mortality. Limitations Vital status was unknown in 261 participants from the original cohort. Conclusions Kidney disease marked by albuminuria or increased cystatin C level appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
Lower urinary tract symptoms (LUTS) are associated with frailty phenotype, a risk factor for functional decline. Our objective was to determine the association between baseline LUTS and 2-year risk ...of new functional limitation among older men.
We analyzed data from the Osteoporotic Fractures in Men (MrOS) study with baseline at Year 7 and follow-up through Year 9. Participants included 2716 community-dwelling men age ≥ 71 years without any baseline self-reported functional limitation. LUTS severity (American Urologic Association Symptom Index) was classified as none/mild (score 0-7), moderate (8-19), and severe (20-35). At baseline and follow-up, men reported their ability to complete several mobility, activities of daily living (ADLs), and cognition-dependent tasks. Risk was estimated for 3 incident functional limitation outcomes: (1) mobility (any difficulty walking 2-3 blocks or climbing 10 steps), (2) ADL (any difficulty bathing, showering, or transferring), and (3) cognition-dependent (any difficulty managing money or medications). We used Poisson regression with a robust variance estimator to model adjusted risk ratios (ARR) and 95% CIs controlling for age, site, and comorbidities; other demographic/lifestyle factors did not meet criteria for inclusion.
Overall, the 2-year risk was 15% for mobility, 10% for ADLs, and 4% for cognition-dependent task limitations. Compared to none/mild LUTS, risk of incident mobility limitations was increased for moderate (ARR = 1.35, 95% CI: 1.12, 1.63) and severe LUTS (ARR = 1.98, 95% CI: 1.48, 2.64). Men were also at higher risk for incident ADL limitations if they reported moderate (ARR = 1.32, 95% CI: 1.05, 1.67) and severe LUTS (ARR = 1.62, 95% CI: 1.07,2.43). Results were somewhat attenuated after adjusting for the frailty phenotype but remained statistically significant. LUTS were not associated with incident cognition-dependent task limitations.
LUTS severity is associated with incident mobility and ADL limitations among older men. Increased clinical attention to risk of functional limitations among older men with LUTS is likely warranted.
While HIV infection is associated with increased cardiovascular risk, benefit from statin is not well established in HIV-infected adults. We assessed whether statins are associated with a decrease in ...carotid artery intima-media thickness (cIMT) progression and all-cause mortality in HIV-infected adults who are at elevated ASCVD risk and recommended for statins.
Carotid IMT was measured at baseline and follow-up in 127 HIV-infected adults who meet ACC/AHA criteria to be on statins. Inverse probability of treatment weighting (IPTW) was used to address selection bias. Multivariable models were used to control for baseline characteristics.
28 subjects (22%) were on statins and 99 subjects (78%) were not. Mean cIMT at baseline was 1.2 mm (SD = 0.34) in statin users and 1.1 mm (SD = 0.34) in non-users, and the multivariable adjusted difference was 0.05mm (95%CI -0.11, 0.21 p = 0.53). After 3.2 years of follow-up, average cIMT progression was similar in statin users and non-users (0.062mm/yr vs. 0.058 mm/yr) and the multivariable adjusted difference over the study period was 0.004 mm/yr (95% CI -0.018, 0.025, p = 0.74). All-cause mortality appeared higher in non-statin users compared with statin users, but the difference was not significant (adjusted HR = 0.74, 95%CI 0.17-3.29, p = 0.70).
In a HIV cohort who had elevated ASCVD risk and meet ACC/AHA criteria for statins, treatment with statins was not associated with a reduction in carotid atherosclerosis progression or total mortality. Future studies are needed to further explore the impact of statins on cardiovascular risk in the HIV-infected population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world settings are unknown.
Intensive pharmacokinetic studies of ...tenofovir in a large, diverse cohort of HIV-infected women over 24 h at steady state were performed and factors that influenced exposure assessed by areas under the concentration-time curves (AUCs) identified.
HIV-infected women (n = 101) on tenofovir-based therapy underwent intensive 24-h pharmacokinetic sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight, and BMI were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFRs) prior to starting tenofovir were estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using both creatinine and cystatin-C measures.
The median (range) of tenofovir AUCs was 3350 (1031-13 911) ng × h/ml. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, P = 0.002), increasing age (1.21-fold increase per decade, P = 0.0007), and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70 ml/min, P = 0.0075).
Concomitant ritonavir use, increasing age, decreasing BMI, and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
Background South Asian individuals have increased cardiovascular disease and mortality risks. Reliance on creatinine- rather than cystatin C-based estimated glomerular filtration rate (eGFRcys) may ...underestimate the cardiovascular disease risk associated with chronic kidney disease. Methods and Results Among 7738 South Asian UK BioBank participants without prevalent heart failure (HF) or atherosclerotic cardiovascular disease, we investigated associations of 4 eGFRcys and creatinine-based estimated glomerular filtration rate categories (<45, 45-59, 60-89, and ≥90 mL/min per 1.73 m
) with risks of all-cause mortality, incident HF, and incident atherosclerotic cardiovascular disease. The mean age was 53±8 years; 4085 (53%) were women. Compared with creatinine, cystatin C identified triple the number of participants with estimated glomerular filtration <45 (n=35 versus n=113) and 6 times the number with estimated glomerular filtration 45 to 59 (n=80 versus n=481). After multivariable adjustment, the eGFRcys 45 to 59 category was associated with higher risks of mortality (hazard ratio HR, 2.38 95% CI, 1.55-3.65) and incident HF (sub-HR sHR, 1.87 95% CI, 1.09-3.22) versus the eGFRcys ≥90 category; the creatinine-based estimated glomerular filtration rate 45 to 59 category had no significant associations with outcomes. Of the 7623 participants with creatinine-based estimated glomerular filtration rate ≥60, 498 (6.5%) were reclassified into eGFRcys <60 categories. Participants who were reclassified as having eGFRcys <45 had higher risks of mortality (HR, 4.88 95% CI, 2.56-9.31), incident HF (sHR, 4.96 95% CI, 2.21-11.16), and incident atherosclerotic cardiovascular disease (sHR, 2.29 95% CI, 1.14-4.61) versus those with eGFRcys ≥90; those reclassified as having eGFRcys 45 to 59 had double the mortality risk (HR, 2.25 95% CI, 1.45-3.51). Conclusions Among South Asian individuals, cystatin C identified a high-risk chronic kidney disease population that was not detected by creatinine and enhanced estimated glomerular filtration rate-based risk stratification for mortality, incident HF, and incident atherosclerotic cardiovascular disease.
Background
Compared to uninfected adults, HIV‐infected adults on antiretroviral therapy are at increased risk of cardiovascular disease. Given the increase in T‐cell dysfunction, inflammation, and ...coagulation in HIV infection, microvascular dysfunction is thought to contribute to this excess cardiovascular risk. However, the relationships between these variables remain undefined.
Methods and Results
This was a cross‐sectional study of 358 HIV‐infected adults from the SCOPE cohort. Macrovascular endothelial function was assessed using flow‐mediated dilation of the brachial artery and microvascular function by reactive hyperemia. T‐cell phenotype was determined by flow cytometry. Plasma markers of inflammation (tumor necrosis factor‐α, interleukin‐6, high‐sensitivity C‐reactive protein, sCD14) and coagulation (fibrinogen, D‐dimer) were also measured. In all HIV+ subjects, markers of inflammation (tumor necrosis factor‐α, high‐sensitivity C‐reactive protein), coagulation (D‐dimer) and T‐cell activation (CD8+PD1+, CD4+interferon+cytomegalovirus‐specific) were associated with worse reactive hyperemia after adjusting for traditional cardiovascular risk factors and co‐infections. In treated and suppressed subjects, tumor necrosis factor‐α and CD8+PD1+ cells remained associated with worse reactive hyperemia after adjustment. Compared to the untreated subjects, CD8+PD1+ cells were increased in the virally suppressed group. Reactive hyperemia was predictive of flow‐mediated dilation.
Conclusions
CD8+PD1+ cells and tumor necrosis factor‐α were associated with microvascular dysfunction in all HIV+ subjects and the treated and suppressed group. Additionally, D‐dimer, high‐sensitivity C‐reactive protein, sCD‐14, and interleukin‐6 were associated with microvascular dysfunction in all HIV+ subjects. Although T‐cell dysfunction, inflammation, and microvascular dysfunction are thought to play a role in cardiovascular disease in HIV, this study is the first to look at which T‐cell and inflammatory markers are associated with microvascular dysfunction in HIV‐infected individuals.
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